Muscle Circulation Research Articles

A phosphodiesterase 3 inhibitor, K-134, improves hindlimb skeletal muscle circulation in rat models of peripheral arterial disease

ObjectiveCilostazol is a phosphodiesterase (PDE)3 inhibitor used to treat peripheral arterial disease with intermittent claudication, as there is clinical evidence that it improves treadmill exercise capacity. However, details of the mechanism underlying this enhanced walking capacity remain to be elucidated. MethodsBased on the hypothesis that PDE3 inhibitors improve peripheral microcirculation in the hindlimbs via vascular smooth muscle relaxation and antiplatelet effects, we examined the effects of a more potent and selective PDE3 inhibitor, K-134, in rat models of peripheral arterial disease (PAD). ResultsIn a hindlimb ischemia model established by bilateral femoral artery occlusion, oral administration of K-134 for 27 days significantly increased blood flow in hindlimb skeletal muscle after exercise induced by electrical stimulation of the sciatic nerve. Moreover, K-134 enlarged the luminal area of intramuscular arteries and prevented rarefaction of capillary density in the gastrocnemius muscle. These effects were observed without pre-administration on the day following the last administration, suggesting that vasodilatory, antiplatelet and angiogenic activities of K-134 were indirectly responsible for the long-term beneficial effects. In fact, K-134 dose-dependently induced relaxation of rat femoral arteries in vitro, and inhibited rat platelet aggregation ex vivo. Interestingly, in a laurate-induced peripheral vascular injury model, oral administration of K-134 for 6 days prevented progression of hindlimb necrosis. ConclusionThese findings suggest that the beneficial effects of PDE3 inhibitors on walking capacity are due to increased hindlimb skeletal muscle blood flow via intramuscular artery enlargement, and that K-134 is a promising drug for PAD associated with platelet hyperaggregability.

Cardiovascular manifestations of acute nitrite intoxication in laboratory rats

The systemic and peripheral hemodynamics was studied in male white rats under conditions of acute nitrite hypoxia (subcutaneous administration of sodium nitrite at doses of 1, 3, and 5 mg/100 g body mass). By the electrocardiographic, rheographic, and other methods there were recorded the heart rate (HR), minute circulation volume (MCV), cardiac output (CO), skeletal muscle circulation (SMC), brain circulation (BC), and systemic arterial pressure (AP). Nitrite was shown to produce a fast, dose-dependent AP decrease accompanied by a decrease of MCV due to development of bradycardia and a fall of CO. At the phase of the steady hypotension, CO increased due to a significant rise of CO on the background of the continuing bradycardia. The systemic circulatory effects of NaNO2 were found to be accompanied by a redistribution of peripheral circulation in the form of a dose-dependent increase of BC and a sharp fall of MCV. It was shown that 1-1.5 h after the nitrite injection the parameters of systemic and peripheral hemodynamics approached the initial levels. Possible triggering mechanisms of the initial stage of the rat cardiovascular adaptation to conditions of acute nitrite hypoxia are discussed.

Not a fine wine: the ATP hypothesis may not get better with age

Not a fine wine: the ATP hypothesis may not get better with age

Effect of gender on training-induced vascular remodeling in SHR

There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise.

Hypoxia: just say NO?

Hypoxia: just say NO?

Transient receptor potential A1 channel contributes to activation of the muscle reflex

This study was undertaken to elucidate the role played by transient receptor potential A1 channels (TRPA1) in activating the muscle reflex, a sympathoexcitatory drive originating in contracting muscle. First, we tested the hypothesis that stimulation of the TRPA1 located on muscle afferents reflexly increases sympathetic nerve activity. In decerebrate rats, allyl isothiocyanate, a TRPA1 agonist, was injected intra-arterially into the hindlimb muscle circulation. This led to a 33% increase in renal sympathetic nerve activity (RSNA). The effect of allyl isothiocyanate was a reflex because the response was prevented by sectioning the sciatic nerve. Second, we tested the hypothesis that blockade of TRPA1 reduces RSNA response to contraction. Thirty-second continuous static contraction of the hindlimb muscles, induced by electrical stimulation of the peripheral cut ends of L(4) and L(5) ventral roots, increased RSNA and blood pressure. The integrated RSNA during contraction was reduced by HC-030031, a TRPA1 antagonist, injected intra-arterially (163 ± 24 vs. 95 ± 21 arbitrary units, before vs. after HC-030031, P < 0.05). Third, we attempted to identify potential endogenous stimulants of TRPA1, responsible for activating the muscle reflex. Increases in RSNA in response to injection into the muscle circulation of arachidonic acid, bradykinin, and diprotonated phosphate, which are metabolic by-products of contraction and stimulants of muscle afferents during contraction, were reduced by HC-030031. These observations suggest that the TRPA1 located on muscle afferents is part of the muscle reflex and further support the notion that arachidonic acid metabolites, bradykinin, and diprotonated phosphate are candidates for endogenous agonists of TRPA1.

근피로에 의한 하지 대퇴직근의 경직도 분석을 위한 근전도 변화에 관한 연구

근경직으로 인한 질병을 판단하기 위한 새로운 비침습적 초음파 근경직도 측정 시스템을 검증하기 위해 근경직 발생시 근전도의 변화를 분석하였다. 근경직 유발을 위해 하지 대퇴직근에서 등척성 운동을 실시하였다. 실험 프로토콜에 따라 실험을 반복 실시하였다. 이때 바이오시스템3를 이용하여 무릎관절토크의 크기 및 토크를 실시간으로 측정하였다. 또한 대퇴직근에서 근전도 측정 시스템으로 근전도를 측정하였다. 피검자는 실험 프로토콜에 따라 최초 무릎관절 토크의 최대수의적 등척성수축(MVC : maximal voluntary contraction)을 측정하고,. MVC의 50%에서 -5%로 떨어질때까지 등척성 운동을 지속하였다. 근경직 유발시 근전도 신호를 신호처리 과정을 거쳐 중앙주파수변동과 실효값 변화로 나타내었으며, 이러한 결과가 근경직도 측정 시스템의 결과와 유의함을 보였다. When the muscle is contracted by continuous and same, the force takes fatigue and stiffness. The aim of this study was to know how the fatigue and muscle stiffness change during an isometric contraction. Surface Electro myography(EMG) signal monitoring system and ultrasonic transducer set up the same muscle stem, subjects contract his right femoris muscle by submaximal isometric contraction(50% of MVC) until exhaustion. Before and after the test, muscle stiffness was measured and EMG was measured during the contraction. As time goes by, muscle fatigue was increased. and the stiffness was shown strongly after the contraction. These results show if the muscle becomes more and more fatigued, the circulation of muscle is delayed although the contraction doesn't happen. So muscle stiffness is increased.

Aberrant Perfusion of the Serratus Anterior Muscle Flap: Report of Two Cases and a Review of the Literature

Free serratus anterior muscle flap, classified as Mathes-Nahai type III, is a versatile and frequently preferred choice for soft tissue coverage of small to moderate-sized defects owing to its reliable circulation pattern; however, some anatomic variations in the flap vascularity can result in partial flap loss. Here we present two cases with free serratus anterior muscle transfer where the distalmost portion of the flap was not perfused by the thoracodorsal pedicle. The most likely explanation seems to be the large flap size and the lack of distal interconnections between lateral thoracic artery and thoracodorsal artery branches. Our clinical experience suggests that anatomic variations of serratus anterior muscle circulation might end up with distal perfusion loss if a large flap is to be harvested.

Excessive sympathetic activation in heart failure with chronic renal failure: role of chemoreflex activation

Sympathetic activation contributes both to the initiation and progression of heart failure. The role of chronic renal failure (CRF) in determining sympathetic overactivity in chronic heart failure (CHF) patients is unknown. We tested the hypothesis that in CHF patients, CRF could lead to increase sympathetic activity through tonic activation of excitatory chemoreceptor afferents. We conducted a double-blind, randomized, vehicle-controlled study to examine the effect of chemoreflex deactivation on muscle sympathetic nerve activity in CHF patients with or without CRF. We compared effect of breathing 100% oxygen for 15 min in 15 stable CHF patients with CRF and 15 control CHF patients matched for age, sex, blood pressure and BMI. The baseline muscle sympathetic nerve activity was significantly elevated in CHF patients with CRF as compared with simple CHF patients (61 +/- 3 versus 42 +/- 4 bursts/min; P < 0.01). Administration of 100% oxygen led to a significant decrease in muscle sympathetic nerve activity in CHF patients with CRF (from 61 +/- 3 to 55 +/- 4 bursts/min; P < 0.05). By contrast, neither 100% oxygen nor room air changed muscle sympathetic nerve activity or hemodynamics in patients with solely CHF. Tonic activation of excitatory chemoreflex afferents contributes to increased efferent sympathetic activity to muscle circulation and to blood pressure control in CHF patients with CRF. These findings may have important implications for understanding how CRF contributes to the progression of CHF and increases morbidity and mortality in CHF patients.

No Impaired Hemoglobin Oxygenation in Forearm Muscles of Patients With Chronic CRPS-1

Physiotherapy is considered an important treatment option in patients with upper limb complex regional pain syndrome type-1 (CRPS-1). In case of chronic CRPS-1, exercise therapy of the affected limb forms an important part of the physiotherapeutic program. We investigated whether muscle loading in chronic CRPS-1 patients is associated with impairments in muscle circulation of the forearm of the affected limb. Thirty patients with chronic CRPS-1 unilaterally affecting their upper limbs, and 30 age-matched and sex-matched control participants were included in this study. Local muscle blood flow and hemoglobin oxygenation were measured by near infrared spectroscopy within the muscles of the forearm at rest, after 1-minute isometric handgrip exercises, and after arterial occlusion. Main outcome parameters were: local muscle blood flow, O2 consumption (mVO2), and postischemic reoxygenation (ReOx). We found no differences in baseline muscle blood flow, mVO2, and ReOx between the affected CRPS-1, unaffected CRPS-1, and control arms. After exercise, mVO2 of the affected CRPS-1 arms was not different from the clinically unaffected CRPS-1 arms. Furthermore, in comparison with the control arms, unaffected CRPS-1 arms showed no difference in mVO2 or ReOx. Muscle loading does not seems to be related to impairments in muscle oxygen uptake in forearm muscles of upper limbs affected by chronic CRPS-1. Our results suggest that exercise therapy can be safely used in physiotherapeutic training programs for chronic CRPS-1 of the upper limb.

Insulin Resistance Impairs Endothelial Function but not Adrenergic Reactivity or Vascular Structure in Fructose‐fed Rats

Obesity and diabetes are major risk factors for the development of vascular disease in the lower limbs. Previous studies have demonstrated reduced nitric oxide (NO)-mediated vasodilation, increased adrenergic constriction, and inward, atrophic remodeling in the limb circulation of obese Zucker rats, but the component of the "metabolic syndrome" driving these changes is unclear. Because insulin resistance precedes the state of frank diabetes, the current study hypothesized that insulin resistance independent of obesity induced by fructose feeding would impair microvascular function in the skeletal muscle circulation in lean Zucker rats (LZR). A 66% fructose diet impaired glucose tolerance and induced moderate insulin resistance with no changes in whole-body hemodynamics of anesthetized rats (FF-LZR), compared to control LZR. NO-mediated vasodilation of isolated gracilis arteries, assessed in vitro with acetylcholine and sodium nitroprusside, was reduced approximately 20% in FF-LZR vs. LZR. NO-independent cGMP-mediated vasodilation was unimpaired. Pretreatment of isolated vessels with the superoxide scavenger, tempol, improved responses to both vasodilators. Reactivity to adrenergic stimulation was unaltered in FF-LZR vs. LZR, although constriction to endothelin was increased. Structural and passive mechanical characteristics of isolated gracilis arteries were similar in both LZR and FF-LZR. Taken together, these findings indicate that moderate insulin resistance is sufficient to impair endothelial function in an oxidant-dependent manner in the rat hindlimb circulation. Other aspects of skeletal muscle vascular function documented in obese models, specifically adrenergic tone and inward remodeling, must reflect either severe insulin resistance or other aspects of obesity. The factors accounting for nonendothelial vasculopathies remain unknown.

Reduced Leg Muscle Oxygenation During Underwater Treadmill Walking

Central circulation and whole body metabolism adjustments, in particular, have been investigated using respiratory gas analysis and heart rate (HR) measurement. However, local muscle circulation and oxidative metabolism have never been investigated during underwater walking. PURPOSE: The purpose of this study was to determine muscle oxygenation in the lower extremities during underwater walking on a treadmill. METHODS: Eight healthy men (age 25 ± 3 y.r., height 175 ± 4 cm, weight 69.6 ± 5.7 kg, BMI 23 ± 2, VO2max 56.7 ± 5.9 ml/kg/min) performed a treadmill walking test twice, once in water and once on land. Each subject began underwater treadmill walking at 1.0 km/h in 0.5 km/h increments at intervals on 2 minutes until 3.5 km/h. Each subject also began land-treadmill walking at 2.0 km/h in 1.0 km/h increments at intervals of 2 minutes until 7.0 km/h. The HR was continuously monitored by a telemeter. Muscle electromyographic (EMG) activity was monitored in the vastus lateralis (VL) and the medial head of the gastrocnemius (MG). The muscle oxygenation level was continuously monitored in the VL and the MG using near-infrared spectroscopy (NIRS). RESULTS: Muscle oxygenation decreased greater during underwater walking than during land walking both in the VL and in the MG. There is no significant difference in the EMG activity between the two conditions in both muscles. The combination of EMG and NIRS results indicate that the greater decrease in the muscle oxygenation is due to reduced muscle perfusion resulting from the facilitated venous return to central circulation during underwater walking. CONCLUSIONS: The results of this study indicate that the greater decrease in the muscle oxygenation is due to reduced muscle perfusion resulting from facilitated venous return to central circulation during underwater walking. Supported by the Mizuno Sports Foundations (2006) and by the twenty-first century COE program, Ministry of Education, Culture, Sports, Science and Technology (2002-2006 Nishihira Project), Japan.

Modulation of Vascular O2 Responses by Cytochrome 450‐4A ω‐Hydroxylase Metabolites In Dahl Salt‐Sensitive Rats

This study evaluated the role of the 20-HETE/cytochrome P450-4A omega-hydroxylase (CYP450-4A) system in microvascular regulation in the skeletal muscle circulation following short-term (three-day) exposure to a high-salt (HS) diet in Dahl salt-sensitive (SS) rats. The effects of inhibiting CYP450-4A on resting diameter, O(2)-induced constriction, and vasodilator responses to acetylcholine (ACh) and the nitric oxide (NO) donor, sodium nitroprusside (SNP), were evaluated in cremasteric arterioles of SS rats fed a low- (LS; 0.4% NaCl) or high-salt (HS; 4% NaCl) diet for three days. The HS diet upregulated CYP450-4A mRNA expression and led to an enhanced constriction of arterioles in response to elevated PO(2) in SS rats, which could be blocked by inhibiting CYP450-4A enzymes with dibromododecenyl methylsulfimide (DDMS). DDMS also inhibited resting tone significantly in SS rats fed the HS, but not the LS, diet, despite similar resting diameters and active tone in the two groups. Arteriolar dilations in response to ACh and SNP were similar in SS rats fed the LS vs. the HS diet and were unaffected by DDMS. These findings suggest that CYP450-4A enzymes contribute to resting tone and to an enhanced response to elevated PO(2) in arterioles of Dahl-SS rats fed the HS diet.

TRPA1 is part of muscle reflex

This study was undertaken to elucidate the role played by transient receptor potential A1 channels (TRPA1) in evoking the muscle reflex, a sympathoexcitatory drive originating from contracting muscle. In the first set of experiments, we tested if stimulation of TRPA1 on muscle afferents reflexly increases sympathetic nerve activity (SNA). In 13 decerebrate rats, allyl isothiocyanat (AITC, 50 µg·kg−1), a TRPA1 agonist, was injected into the hindlimb muscle circulation, and led to a 46% increase in renal SNA (RSNA). The response was prevented by intra‐arterial injection of HC‐030031 (3 mg), a TRPA1 selective blocker (n=8). The effect of AITC was a reflex because the response was prevented by section of the sciatic nerve (n=5). In the second set of experiments, we tested if blockade of TRPA1 reduces RSNA response to contraction. In 8 decerebrate rats, 30 s static contraction of hindlimb muscle, induced by electrical stimulation of the cut ends of L4 and L5 ventral roots, increased RSNA and blood pressure. The increase in RSNA seen during the late period of contraction (10‐30 s after onset of contraction) was reduced by HC‐030031 injected intra‐arterially (32±5 vs. 14±3 arbitrary units; before vs. after HC‐030031; P&lt;0.05). Taken together, we suggest that TRPA1 located on muscle afferents is part of the muscle reflex. Physiological stimulants/mediators of TRPA1 need to be explored. Supported by AHA BGIA 0865416D (SK).

Circulatory system in chicken skeletal muscle in the second half of embryogenesis: Shape, blood flow, and vascular reactivity

A restructuring of the capillary bed-from the embryonic structure with a three-dimensional network of wide and long protocapillaries to the mature structure with high density of thin and short capillaries along the fibers-has been demonstrated in the chick skeletal muscle on embryonic days 10-19 by morphometric analysis. In this case, the volumetric flow rate and capillary luminal area per cm3 of the muscle remained unaltered, while the blood volume in it significantly dropped. The response of muscle circulation to nitroprusside (increase) and noradrenaline (decrease) appeared in 19-day-old embryos, but this response could develop only under conditions of initially low or high bloodstream, respectively. We propose that the arterial trunk lumen area to the total capillary lumen area remains constant as the intraorganic circulation is formed, which provides for the required linear blood velocity in capillaries.

Effects of Manual Acupuncture with Sparrow Pecking on Muscle Blood Flow of Normal and Denervated Hindlimb in Rats

In clinical practice, it has been thought that acupuncture might serve to wash out pain-generating metabolic end-products by improving blood circulation in muscles. We investigated the effects of manual acupuncture (MA) on muscle blood flow (MBF) of normal and denervated hindlimbs in rats. Sprague-Dawley rats (n=100) anaesthetised with urethane (1.2g/kg ip) were used. Manual acupuncture with sparrow pecking (SP) at different doses (1, 10 or 30 pecks) was given to the right ventral hindlimb muscles (tibial anterior and extensor digitorum longus muscles) or the right dorsal hindlimb muscles (gastrocnemius, plantaris and soleus muscles). MBF with or without MA was measured using the radiolabelled microsphere technique. The blood pressure was recorded through the right common carotid artery until MBF measurement started. Denervation of hindlimb was conducted by cutting the sciatic and femoral nerves. In normal rats, significantly increased MBF after MA were observed only in muscles which were penetrated by an acupuncture needle. The size of the increase depended on the number of times of pecking and seemed to be sustained at least until 60 minutes after MA. However, the increase was observed after both acute and chronic denervation. On the other hand, the mean arterial blood pressure (MAP) did not change significantly before, during or after MA. These results suggest that MA could increase muscle blood flow locally in a dose-dependent manner and that this increase may be caused by local vasodilators, as well as the axon reflex. A further study is needed to elucidate the mechanism.

Graded sympatholytic effect of exogenous ATP on postjunctional α‐adrenergic vasoconstriction in the human forearm: implications for vascular control in contracting muscle

Recent evidence suggests that adenosine triphosphate (ATP) can inhibit vasoconstrictor responses to endogenous noradrenaline release via tyramine in the skeletal muscle circulation, similar to what is observed in contracting muscle. Whether this involves direct modulation of postjunctional alpha-adrenoceptor responsiveness, or is selective for alpha(1)- or alpha(2)-receptors remains unclear. Therefore, in Protocol 1, we tested the hypothesis that exogenous ATP can blunt direct postjunctional alpha-adrenergic vasoconstriction in humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses to local intra-arterial infusions of phenylephrine (alpha(1)-agonist) and dexmedetomidine (alpha(2)-agonist) during moderate rhythmic handgrip exercise (15% maximum voluntary contraction), during a control non-exercise vasodilator condition (adenosine), and during ATP infusion in eight young adults. Forearm hyperaemia was matched across all conditions. Forearm vasoconstrictor responses to direct alpha(1)-receptor stimulation were blunted during exercise versus adenosine (DeltaFVC = -11 +/- 3% versus -39 +/- 5%; P< 0.05), and were abolished during ATP infusion (-3 +/- 2%). Similarly, vasoconstrictor responses to alpha(2)-receptor stimulation were blunted during exercise versus adenosine (-13 +/- 4% versus -40 +/- 8%; P< 0.05), and were abolished during ATP infusion (-4 +/- 4%). In Prototol 2 (n = 10), we tested the hypothesis that graded increases in ATP would reduce alpha(1)-mediated vasoconstriction in a dose-dependent manner compared with vasodilatation evoked via adenosine. Forearm vasoconstrictor responses during low dose adenosine (-38 +/- 3%) and ATP (-33 +/- 2%) were not significantly different from rest (-40 +/- 3%; P> 0.05). In contrast, vasoconstrictor responses during moderate (-22 +/- 6%) and high dose ATP (-8 +/- 5%) were significantly blunted compared with rest, whereas the responses during adenosine became progressively greater (moderate = -48 +/- 4%, P = 0.10; high = -53 +/- 6%, P< 0.05). We conclude that exogenous ATP is capable of blunting direct postjunctional alpha-adrenergic vasoconstriction, that this involves both alpha(1)- and alpha(2)-receptor subtypes, and that this is graded with ATP concentrations. Collectively, these data are consistent with the conceptual framework regarding how muscle blood flow and vascular tone are regulated in contracting muscles of humans.

Commentaries on Viewpoint: The human cutaneous circulation as a model of generalized microvascular function

Commentaries on Viewpoint: The human cutaneous circulation as a model of generalized microvascular function

Very low frequency blood pressure fluctuations: not only myogenic responsiveness

Very low frequency blood pressure fluctuations: not only myogenic responsiveness

Nicotine increases chemoreflex sensitivity to hypoxia in non-smokers

The peripheral chemoreflex contributes to cardiovascular regulation and represents the first line of defence against hypoxia. The effects of nicotine on chemoreflex regulation in non-smoking humans are unknown. We conducted a prospective, randomized, crossover, and placebo-controlled study in 20 male non-smokers to test the hypothesis that nicotine increases chemoreflex sensitivity. The effects of two intakes of 2 mg nicotine tabs and placebo on sympathetic nerve activity to muscle circulation (muscle sympathetic nerve activity; MSNA), minute ventilation (Ve), blood pressure and heart rate were assessed during normoxia, moderate isocapnic hypoxia, hyperoxic hypercapnia and an isometric handgrip in 10 subjects. Maximal end-expiratory apnoeas were performed at baseline and at the end of the fifth minute of hypoxia. In a second experimental setting, we studied the ventilatory response to a more marked isocapnic hypoxia in 10 other volunteers. Mean MSNA and Ve were not modified by nicotine during the 5 min of normoxia or moderate hypoxia. In the presence of nicotine MSNA was related to oxygen desaturation (P < 0.01). The sympathoexcitatory effects of nicotine became especially evident when apnoeas achieved oxygen saturations less than 85% (511 +/- 44% increase in MSNA after the first intake, and 436 +/- 43% increase after the second intake versus 387 +/- 56% and 338 +/- 31% with placebo, respectively, P < 0.05). Nicotine also increased the ventilatory response compared with placebo when oxygen saturation decreased to less than 85% (P < 0.05). This is the first study to demonstrate that nicotine increases peripheral chemoreflex sensitivity to large reductions in arterial oxygen content in healthy non-smokers.